Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Abstract

BACKGROUND Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P = 0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02). At 72 months, Kaplan–Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P = 0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530.)

Cryopreservation of Hematopoietic Stem Cells: Emerging Assays, Cryoprotectant Agents, and Technology to Improve Outcomes

“…According to the Worldwide Network for Blood and Marrow Transplantation (WBMT), one million HSCTs had been performed by the end of 2012 [4]. In addition to conventional uses of HSCT for the treatment of hematologic malignancies, clinical uses have expanded in recent years to include treatment of severe scleroderma [5], diabetes [6], metabolic disorders [7], and even delivery of gene therapy [7, 8]. …”

Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation

“…25 The eligibility criteria and characteristics of patients enrolled were notably similar among the three trials (Table 1) All three trials demonstrated a benefit in the AHCT arm with respect to their primary endpoints (clinical improvement in ASSIST, event-free survival in ASTIS trial and change in global rank composite score in SCOT trial). Also, patients on the AHCT arm had better overall survival and a lower rate of disease progression.…”

“…A subsequent systematic review and meta-analysis included three randomized trials (including SCOT trial) and one comparative observational study. 17, 23–25, 27 The control arm was monthly cyclophosphamide in all three trials and the majority of patients in the observational study. Compared to controls, patients receiving AHCT experienced lower all-cause mortality (risk ratio [RR] 0.50, [95% confidence intervals, 0.33–0.75] P=0.0007), and improved skin thickness, forced vital capacity, total lung capacity, and quality of life.…”

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

“…For example, in patients with systemic sclerosis, autologous HSCT was found to be associated with stabilization of pulmonary hypertension in affected patients [18]. Additionally, a 5-year post-transplant follow-up study of this same patient cohort demonstrated a trend towards improved lung function parameters, such as the diffusing capacity of lung for carbon monoxide (DLCO) [19], while a more recent clinical trial showed that, in patients with scleroderma, stem cell transplantation can prevent the development of pulmonary hypertension [20]. Similar disease remission following HSCT has been noted in patients with pulmonary hypertension secondary to systemic lupus erythematosus [21,22].…”